One of the major obstacles to developing a HIV vaccine is defining adjuvants and immunogens that induce persistent HIV antigen specific systemic and mucosal humoral responses of high magnitude. Our recent studies evaluating a novel TLR7/8 ligand (3M052) from 3M Pharmaceuticals formulated in biodegradable synthetic polymer nanoparticles in RMs has for the first time yielded HIV Env specific long-lived plasma cells (LLPCs) in the macaque bone marrow for close to one year post final vaccination. The presence of LLPCs correlated significantly with binding, neutralizing and ADCC activity bearing antibody responses that also persisted at high magnitude for a year. Robust and persistent germinal center, follicular t helper cells and lymph node resident plasma cells were also observed in draining lymph nodes in these macaques. Finally, the persistent response was observed to be dependent on the presence of the novel 3M052 adjuvant alone and combining with a TLR4 agonist did not further enhance immune responses in contrast to our observations in mice. However, we have faced considerable challenges in translating our in house developed polymer particle formulations in industrial scale up for human use. Therefore, building on our proof of concept studies, the goal of the current proposal is to: a) systematically evaluate a clinical formulation (cGMP scalable oil emulsion based nanoparticle) developed in partnership with 3M pharmaceuticals and the Infectious Disease Research Institute (IDRI) in its ability to induce these potent Env specific LLPCs in macaques for expedited translation for use in humans and b) carefully dissect the innate and B cell based molecular mechanisms by which the 3M052 adjuvant is capable of promoting Env specific LLPCs and long lived antibody responses.